This program is a long-term prospective study focused upon an understanding of the relationship between various immunogenetic factors, overt diabetes and sub-clinical diabetes. In addition, the impact of these immunogenetic and hereditary factors upon glucose tolerance, insulin responses to a variety of perturbations, and growth hormone and glucagon dynamics is being characterized. Also to be examined is the influence of these genetic, metabolic and hormonal disturbances upon lipid metabolism and upon alterations in the morphology of muscle basement membrane. Glycosylated hemoglobin evaluations are also performed and related to the degree of carbohydrate tolerance and intolerance. The model population consists of monozygotic twins, one or both with diabetes and the offspring of conjugal diabetes including those which parents have type 2 (or maturity onset diabetes), other families in which one parent has type 1 (or juvenile onset diabetes) and the other type 2 diabetes and a small series (four families with nine offspring) in which both parents have classical type 1 diabetes. To be developed in relationship to this program would be other immunogenetic probes to characterize the hereditary and immunological aspects of the pathogenesis of diabetes and other techniques for the evaluation of long-term glycosylation that might relate to the development of microangiopathy in these populations. Preliminary studies is monozygotic twins discordant for diabetes relating muscle capillary basement membrane thickness to presence or absence of diabetes have suggested that factors other than abnormal glucose homeostasis (perhaps genetic) may play an important role upon the microvasculature.